Vasodilatory septic shock is characterized by low arterial blood pressure due to vasodilation with decreased systemic vascular resistance (Landry D W, 2001). This is due to hyporesponsiveness of resistance arteries to endogenous vasopressor agents and vasopressor depletion (Landry 2001; Boyle 2000; Leone and Boyle, 2006). Following volume resuscitation exogenous administration of vascular smooth muscle receptor agonists are thus required to maintain blood pressure and critical organ perfusion (The American Heart Association 2000). Catecholamines—usually either dopamine or norepinephrine—are considered the first line agonists of choice, although progressive hyposensitivity to these agonists often leads to progressive increases in catecholamine requirements to maintain blood pressure. This can result in a vicious cycle in which adverse cardiac effects of the catecholamines—including supraventricular tachyarrhythmias and myocardial ischemia—contribute to further increases in catecholamine requirements with mortality rates that approach 100% (Chernow 1986, Goldstein 2000).
It is apparent that vasodilatation and hypotension are due to failure of the vascular smooth muscle to respond to catecholamines (Benedict and Rose, 1992) and addition of the potent endogenous vasoconstrictor arginine vasopressin (AVP), to catecholamine infusions, has recently been shown to be effective in stabilizing blood pressure and catecholamine requirements in patients with catecholamine-resistant vasodilatory shock (Landry 2001, Dunser 2003, Boyle ASA 2006 review lecture). However, vasoconstriction produced by vasopressin, and the synergistic vasoconstriction produced by the combinations of norepinephrine and vasopressin, was, like responses to norepinephrine alone, decreased in vasodilatory shock (Boyle and Leone, 2006). Thus, while there is a well-described vasopressin deficiency in vasodilatory septic shock, the decrease in vasopressin responsiveness also contributes to a state of relative vasopressin insufficiency, similar to the state of relative catecholamine deficiency, in this condition.
The hyporesponsiveness of vascular smooth muscle to receptor agonists is largely due to de novo expression of inducible nitric oxide synthase (iNOS) and excessive production of NO in vascular smooth muscle (Boyle 2000). NO synthase (NOS) inhibitors have been shown to effectively reverse this hyporesponsiveness and treat the life threatening hypotension that occurs in vasodilatory shock (Boyle 2000, Kilborne 1999). Unfortunately, NO is a ubiquitous mediator, and the pervasive effects of the iNOS inhibitors in vasodilatory shock resulted in increased mortality when these agents were administered in human clinical trials (Cobb 1999).
In the absence of any effective alternative, the current approach for the treatment of vasodilatory shock continues to be administration of large doses of vasoconstrictor agonists, typically norepinephrine or combinations of norepinephrine and vasopressin, to maintain blood pressure and critical organ perfusion. Progressive hyposensitivity to these agonists, however, remains a significant clinical problem that can lead to refractory shock with a high mortality. There is a need in the art, therefore, for a treatment of vasodilatory shock that addresses the vascular smooth muscle hyposensitivity to vasocontrictors.